Design, synthesis and in vitro evaluation of L-amino acid esters prodrugs of acyclic nucleoside phosphonates as anti-HBV agent

A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.

Efficacy and safety of oral Chinese herbal medicine combined with nucleoside antiviral drugs against recurrent genital herpes:a systematic review and meta-analysis

Background:To compare the efficacy and safety of Chinese herbal medicine combined with nucleoside antiviral drugs and nucleoside antiviral drugs alone in treating recurrent genital herpes.Methods:PubMed,Embase,Web of Science,Cochrane Library,Chinese Biomedical Literature Database,China National Knowledge Internet,VIP Database,and Wanfang Data were searched from inception to April 2021.Randomized controlled trials on the efficacy and safety of oral Chinese herbal medicine combined with nucleoside antiviral drugs for recurrent genital herpes were collected.All included trials were independently assessed by two reviewers with the Cochrane risk-of-bias tool,and a meta-analysis was conducted using Review Manager 5.4.Results:Compared with the use of nucleoside antiviral drugs alone,combination therapy with oral Chinese herbal medicine plus nucleoside antiviral drugs effectively reduced the herpes recurrence rate after the end of treatment(3 months:P=0.0002;6 months:P<0.00001;1 year:P<0.00001)and the number of recurrences each year(P<0.00001),improved the recurrent Genital Herpes Quality of Life Questionnaire score(P<0.00001),and regulated the levels of interferon-γ,interleukin-2,tumor necrosis factor-α,and T lymphocyte subsets in the peripheral blood,and the difference was statistically significant.Different subgroups reported mixed results with respect to the efficacy in the short term.The incidence of adverse reactions and the time of symptom disappearance between the two groups were not significantly different.Conclusion:Chinese herbal medicine combined with nucleoside antiviral drugs can effectively reduce the recurrence rate of recurrent genital herpes,improve the patient’s quality of life and enhance the body’s immunity.Considering the possible risk of publication bias,more high-quality randomized controlled trials are still needed to verify the conclusions of this article.

Effects of Fuzheng Huayu Capsules combined with nucleoside antiviral drugs on liver and kidney function, serum inflammatory factors, TLR-4, TGF-β1 and aspartate aminotransferase-platelet ratio index in patients with HBV infection and decompensated liver

Objective:To investigate the effect of Fuzheng Huayu Capsule combined with nucleoside antiviral drugs on liver and kidney function,serum inflammatory factors,Toll-like receptor 4(TLR-4),transforming growth factorβ1(TGF-β1)And aspartate aminotransferase-platelet ratio index(APRI).Methods:A total of 144 patients with HBV infection and decompensated cirrhosis were selected.All patients were divided into control group and case group by random number table method,with 72 cases in each group.The control group was given conventional liver protection and antiviral therapy;the case group was supplemented with Fuzheng Huayu Capsule on the basis of treatment in the control group.The changes of liver and kidney function,serum inflammatory factors,TLR-4,TGF-β1 and APRI in the two groups were observed.Results:The total effective rate of the case group was 93.06%,higher than 76.32%of the control group(P<0.05).Case group HBV DNA negative rate,negative rate of hepatitis B virus surface antigen(HBsAg),negative rate of hepatitis B virus e antigen(HBeAg)were significantly higher than the control group(76.39%vs 59.72%,55.56%vs 31.94%,51.39%vs 29.17%),the difference was statistically significant(P<0.05).Alanine aminotransferase(ALT),aspartate aminotransferase(AST),total bilirubin(TBIL),hyaluronic acid(HA),laminin(LN),typeⅢprocollagen after treatment(PCⅢ),typeⅣcollagen(CⅣ),inner diameter of portal vein,inner diameter of splenic vein,spleen thickness,resistance index,urea nitrogen(BUN),creatinine(Cr),interleukin-6(IL-6),interleukin-8(IL-8),high-sensitivity C-reactive protein(hs-CRP),tumor necrosis factor-α(TNF-α),TLR-4,TGF-β1,APRI are lower than before treatment,albumin(ALB)and renal blood The flow rate was higher than before treatment;liver function indicators,liver fibrosis indicators,liver and spleen imaging indicators,renal hemodynamic indicators,serum inflammatory factors,TLR-4 in the case group The improvement of TGF-β1 and APRI.Conclusion:Fuzheng Huayu Capsules combined with nucleoside antiviral drugs have a clear clinical effect on patients with HBV infection and decompensated liver cirrhosis,significantly improve the clinical symptoms of patients,improve liver and kidney function,reduce inflammatory factor production,and can effectively inhibit HBV replication.Certain promotion value is worthy of further clinical research.

Effects of alprostadil combined with nucleoside antiviral drugs on liver function, liver fibrosis markers and serum inflammatory factors in patients with decompensated liver cirrhosis with HBV infection

Objective:To explore the Effects of alprostadil combined with nucleoside antiviral drugs on liver function, liver fibrosis markers and serum inflammatory factors in patients with decompensated liver cirrhosis with HBV infection.Methods: 136 patients with decompensated cirrhosis of HBV infection who were hospitalized in Linxi Hospital of Kailuan General Hospital, Tangshan Infectious Disease Hospital and North China University of Technology Hospital from January to February 2018, 2017 were selected. All patients were divided into control group and case group by random number table method, 68 cases in each group. The control group was treated with routine liver protection and antiviral therapy, while the case group was treated with alprostadil on the basis of the control group. The changes of liver function, liver fibrosis, liver and spleen imaging indexes, anti-virus related indexes and inflammatory factors were observed before and after treatment in the two groups.Results: The total effective rate of the case group was 97.06%, which was significantly higher than that of the control group (85.29%), and the difference was statistically significant. The ALT, AST, TBIL, LN, HA, PCIII, CIV, portal vein diameter, spleen vein diameter, spleen thickness, IL-6, hs-CRP, TNF-α and TGF-β1 were significantly lower in the case group than in the control group. ALB, HBV DNA conversion rate, HBsAg negative rate, and HBeAg negative rate were significantly higher than the control group, the difference was statistically significant. Conclusion: Alprostadil combined with nucleoside antiviral drugs can significantly improve the decompensation of HBV infection Liver function in patients with cirrhosis, reduce the degree of liver fibrosis, inhibit the production of serum inflammatory factors, and can effectively inhibit HBV replication, clinical efficacy is significant, with certain clinical application value.

Anti-Hepatitis B Virus Drugs in Clinical and Preclinical Development

Up to date, there are two types of drugs approved to treat hepatitis B： interferons and nucleos （t） ide analogues. However, the therapies are limited in the clinical context because of the negative side effects of interferon-or and the development of substantial viral resistance to nucleos （t） idic inhibitors. Therefore, new drugs with novel structures and mechanisms are needed. In this article, the drugs approved by FDA or the European Commission for treating chronic hepatitis B virus infection, as well as those under clinical trials, and several compounds in preclinical studies are reviewed. Additionally, some potential targets and strategies to combat chronic hepatitis B virus infection are discussed.

New strategies against drug resistance to herpes simplex virus

Herpes simplex virus （HSV）, a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir （ACV） and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets （the DNA helicase/primase （H/P） complex）, new types of molecules （nature products） and new antiviral mechanisms （lethal mutagenesis of Janus-type nucleosides） to fight the drug resistance of HSV.

从“HBF drug watch”看抗HBV药物研制的现状及进展

乙型肝炎病毒(hepatitis B virus,HBV)是全球公众健康的首要危险因素,目前现有的抗病毒治疗方案只能抑制HBV复制,不能完全根除HBV.由于抗丙型肝炎病毒(hepatitis C virus,HCV)的直接抗病毒药物(direct antiviral agents,DAAs)陆续上市,国外许多大的制药公司转向投入抗HBV药物研制.近两年登陆http://www.hepb.org/professionals/hbf_drug_watch.htm网站,抗HBV药物研制更新较以前明显增快.本文将在上述网站上可以查证到的已上市和在研究的抗HBV药物种类、作用机制及未来市场前景进行简要述评及总结.

2019—2022年北京某院HIV-1新发感染者抗病毒治疗前耐药情况分析

目的 了解2019—2022年该院新发1型人类免疫缺陷病毒(HIV-1)感染者中原发耐药水平和流行现状。方法 对2019—2022年HIV-1确认阳性且未行抗病毒治疗的新发感染者进行原发耐药检测。应用反转录/巢式聚合酶链式反应扩增病毒pol基因,进行病毒亚型、主要耐药相关突变和原发耐药率分析等。结果 2019—2022年新发HIV-1感染者进行原发耐药检测比例分别为62.23%(669/1 075)、80.00%(400/500)、 80.78%(500/619)及81.03%(474/585),原始耐药发生比例分别为5.31%(30/565)、6.65%(24/361)、6.59%(30/455)及4.19%(18/430),总耐药比例为5.63%(102/1 811)。蛋白酶抑制剂、核苷类反转录酶抑制剂(NRTIs)、非核苷类反转录酶抑制剂(NNRTIs)耐药率分别为0.11%(2/1 811)、1.44%(26/1 811)、4.91%(89/1 811);NNRTIs类耐药位点主要是V179D/E单独或与其他位点协同出现;NRTIs类耐药位点主要是M184V及K65R。主要感染亚型依次为CRF01_AE[44.56%(807/1 811)]、CRF07_BC[39.54%(716/1 811)]、B亚型[8.28%(150/1 811)]。结论 该院新诊断HIV-1感染者进行原发耐药检测比例逐年上升,近3年来原发耐药率呈下降趋势,原发耐药呈低流行水平,主要原发耐药为NNRTIs及NRTIs耐药。

带量采购政策对我院核苷类抗乙型肝炎病毒药物使用情况的影响

目的分析孝感市中心医院执行带量采购政策对核苷类抗乙型肝炎病毒药物使用情况的影响,为医院药事管理和药物政策制定提供参考。方法提取医院执行带量采购政策前后4种核苷类抗乙型肝炎病毒药物的使用数据,采用药物经济学方法对药品供应目录、药品价格、销售数量、销售金额、用药频度(DDDs)、限定日费用(DDC)和排序比(B/A)等进行回顾性分析。结果执行带量采购政策后,4种核苷类抗乙型肝炎病毒药物的总消耗量增加了73.34%,销售总金额下降了96.49%,总DDDs增加了46.15%,未中选的阿德福韦酯、恩替卡韦和替诺福韦DDC下降比例达10.45%~42.12%。结论执行带量采购政策可以有效减少医疗机构药品费用支出,提高医保基金使用效率,显著减轻患者的用药负担,进一步促进临床合理用药。

血清乙型肝炎表面抗原及乙型肝炎病毒RNA水平在预测核苷(酸)类药物治疗慢性乙型肝炎患者停药后复发中的价值

目的分析乙型肝炎表面抗原(HbsAg)及乙型肝炎病毒RNA(HBV RNA)水平检测对核苷(酸)类药物(NAs)治疗慢性乙型肝炎(CHB)患者停药后复发的预测效果。方法选取2020年1月至2021年1月在赣州市人民医院使用NAs治疗并达到停药标准的80例CHB患者,展开1年随访,根据有无病毒学复发分为复发组和未复发组。采集两组患者血液标本,展开HBV RNA及HBsAg定量检测,分析HBsAg和HBV RNA定量对NAs药物停药后复发的预测价值。结果80例患者复发率17.50%,复发组的停药时HBV DNA载量、停药时HBsAg定量高于未复发组,差异有统计学意义(P<0.05)。复发组停药6、12、18、24个月,HBsAg及HBV RNA定量水平比较,停药24个月HBsAg及HBV RNA定量水平高于其他时间点,差异有统计学意义(P<0.05)。HBV RNA预测疾病复发的敏感度为85.71%,特异度80.30%,HBsAg对应数值为78.57%、89.39%。结论HBsAg和HBV RNA定量对NAs药物停药后CHB复发有预测价值,值得推广。

Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment

Remdesivir(RDV) is the only US Food and Drug Administration(FDA)-approved drug for treating COVID-19.However,RDV can only be given by intravenous route,and there is a pressing medical need for oral antivirals.Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated.We performed an in vitro and in vivo drug metabolism and pharmacokinetics(DMPK) assessment to examine the potential of RDV,and particularly GS-441524,as oral drugs.In our in vitro assessments,RDV exhibited prohibitively low stability in human liver microsomes(HLMs,t1/2=-1 min),with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety.This observation is poorly aligned with any potential oral use of RDV,though in the presence of cobicistat,the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH.Conversely,GS-441524 showed excellent metabolic stability in human plasma and HLMs.In further in vivo studies in CD-1 mice,GS-441524 displayed a favorable oral bioavailability of 57%.Importantly,GS-441524 produced adequate drug exposure in the mice plasma and lung,and was effectively converted to the active triphosphate,suggesting that it could be a promising oral antiviral drug for treating COVID-19.

Synthesis and anti-HBV evaluation of mono L-amino acid ester, mono non-steroid anti-inflammation drug carboxylic ester derivatives of acyclonucleoside phosphonates

A series of mono L-amino acid ester, mono non-steroid anti-inflammation drug （NSAID）, carboxylic ester derivatives of acyclonucleoside phosphonates were prepared by using a ＂one pot synthesis＂ method and their in vitro anti-HBV activity were evaluated in HepG 2.2.15 cells. Compound 9a exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with IC50 and selective index （SI） values of 0.48μmol/L and 763.72, respectively.

八珍汤合化积丸加减联合核苷类药物治疗“正虚血瘀型”乙肝肝硬化继发脾功能亢进的效果

目的:探讨八珍汤合化积丸加减联合核苷类药物治疗“正虚血瘀型”乙肝肝硬化继发脾功能亢进的效果。方法:选取2020年6—12月在武威市凉州医院就诊的西医诊断为“乙型肝炎后肝硬化继发脾功能亢进”、中医辨证为“正虚血瘀型”的96例患者作为研究对象,根据随机数表法分为对照组和观察组,各48例。对照组给予替诺福韦酯,观察组给予替诺福韦酯联合八珍汤合化积丸,比较两组白细胞(WBC)、血小板(PLT),凝血酶原活动度(PTA)、脾脏厚度、门静脉内径变化、肝脏硬度值及临床疗效。结果:治疗前、治疗3个月,两组WBC、PLT、PTA水平及脾脏厚度、门静脉内径比较,差异无统计学意义(P>0.05);治疗6个月,两组WBC、PLT、PTA水平较治疗前升高,脾脏厚度、门静脉内径较治疗前降低,且观察组优于对照组,差异有统计学意义(P<0.05)。两组治疗前肝脏FibroScan弹性值比较,差异无统计学意义(P>0.05);观察组治疗6个月肝脏FibroScan值小于对照组,差异有统计学意义(P<0.05)。观察组总有效率为87.5%,高于对照组的62.5%,差异有统计学意义(P<0.05)。结论:八珍汤和化积丸加减联合核苷类药物治疗“正虚血瘀型”乙肝肝硬化继发脾功能亢进,不仅能改善患者的临床症状,还能提高WBC、PLT,改善PTA,在降低肝脏硬度值及脾脏厚度和门静脉内径方面效果显著。

一线核苷类药物治疗慢性乙型肝炎的文献计量学分析

目的 分析国内外一线核苷类药物治疗慢性乙型肝炎相关文献,了解目前一线核苷类药物治疗慢性乙型肝炎领域的研究现状、前沿热点和趋势。方法 检索2019年至2023年中国知网、维普资讯、万方数据、Web of Science核心合集数据库和PubMed医学文献数据库核心合集,纳入国内文献1 239篇、国外文献967篇,采用NoteExpress和Vosviewer软件进行文献可视化分析,绘制可视化知识图谱。结果 国内高频关键词有肝硬化、纤维化、肝细胞癌等,国外高频关键词有hepatocellular carcinoma、HBsAg、cirrhosis等。结论 国内研究着重于肝病进展及现有治疗方案的优化,合作网络相对集中;国外研究则关注于风险预测模型和长期疗效,合作网络呈多中心化。

真菌产生的新核苷转运抑制剂增强药物的抗肿瘤活性

从南极土壤中分离的一株真菌所产生的抗生素Ｃ３３６８－Ｂ（ＣＢ）有较强的核苷转运抑制活性。ＣＢ显著抑制艾氏腹水癌（ＥＡＣ）细胞的胸苷和尿苷转运，ＩＣ５０分别为７．５和９．６μｍｏｌ·Ｌ－１。用克隆生成法测定，ＣＢ在本身无明显细胞毒性剂量下，能显著增强氨甲蝶呤（ＭＴＸ）、５－氟脲嘧啶（５ＦＵ）和丝裂霉素Ｃ（ＭＭＣ）等抗癌药物对人口腔鳞癌ＫＢ细胞和人肝癌ＢＥＬ－７４０２细胞的杀伤。生长抑制法结果显示，ＣＢ还能部分逆转小鼠白血病Ｌ１２１０／ＭＤＲ细胞对长春新碱（ＶＣＲ）和放线菌素Ｄ（ＡＣＤ）的抗药性。结果提示新核苷转运抑制剂ＣＢ可能应用于肿瘤联合化疗的前景。

核苷类抗病毒药物联合微生态制剂治疗HBV感染失代偿期肝硬化患者的临床效果

目的观察核苷类抗病毒药物联合微生态制剂治疗HBV感染失代偿期肝硬化患者的临床疗效。方法选取2014年1月—2016年1月新疆医科大学第五附属医院消化内科住院的HBV感染失代偿期肝硬化患者82例作为研究对象。采用随机数字表法分为2组,每组41例。对照组给予常规治疗+恩替卡韦分散片,观察组在对照组基础上口服双歧杆菌三联活菌胶囊, 2组均治疗48周。比较2组患者临床疗效、肝功能指标、肝纤维化指标、肝脾影像学指标以及抗病毒相关指标。结果观察组总有效率为95.12%,高于对照组的80.49%(χ~2=4.100,P=0.043);与治疗前比较,2组患者治疗24周、48周后ALT、AST、TBil、LN、HA、PCⅢ、CⅣ、门静脉内径、脾静脉内径、脾脏厚度水平均明显降低,Alb明显升高(P<0.01),且观察组48周后各项指标改善均优于对照组(t/P=16.287/0.000、15.276/0.000、8.482/0.000、5.163/0.002、9.762/0.000、15.262/0.000、14.732/0.000、10.824/0.000、3.647/0.017、11.636/0.000、9.842/0.000);2组HBV-DNA水平显著下降且观察组降低优于对照组(t=5.264,P=0.000),HBV-DNA转阴率、HBeAg转阴率均显著高于对照组(χ~2/P=4.100/0.043、4.479/0.034)。结论核苷类抗病毒药物联合微生态制剂治疗HBV感染失代偿期肝硬化患者具有良好的临床疗效,能够明显改善肝功能、减轻肝纤维化程度,并能有效抑制HBV复制,具有一定的临床推广应用价值。

核苷类抗病毒药物治疗乙肝肝硬化患者的疗效分析

目的观察核苷类抗病毒药物治疗乙肝肝硬化患者的近期疗效及安全性。方法将172例乙肝肝硬化患者按照队列研究法分为治疗组和对照组,每组86例。对照组接受常规治疗,治疗组在对照组基础上加用核苷类抗病毒药物治疗,比较2组患者的近期疗效及并发症发生情况。结果治疗组患者谷草转氨酶(AST)、谷丙转氨酶(ALT)及总胆红素(TBiL)水平显著低于对照组,而白蛋白(Alb)及胆碱酯酶(ChE)水平显著高于对照组,差异有统计学意义;治疗组患者乙型肝炎病毒(HBV)DNA和乙型肝炎e抗原(HBeAg)转阴率,以及HBV DNA下降幅度均显著高于对照组,而自发性腹膜炎发生率显著低于对照组,差异均有统计学意义。结论核苷类抗病毒药物可有效改善乙肝肝硬化患者的肝功能,抑制HBV病毒复制,促使HBeAg转阴。

核苷类抗疱疹病毒药物的研究进展

疱疹病毒可引起多种疾病,如角膜炎、唇疱疹、带状疱疹、生殖器疱疹、脑炎等,目前临床上用于治疗疱疹性疾病的药物主要是以阿昔洛韦为代表的核苷类药物,本文对已上市及正在研究中的核苷类抗疱疹药物及其作用机制作简要介绍。

延续性护理对慢性乙型肝炎患者服用核苷(酸)类药物依从性的影响

目的探讨延续性护理的实施对慢性乙型肝炎患者服用核苷(酸)类药物依从性的影响。方法2015年1-3月,采取便利抽样法选取在第二军医大学长海医院感染科住院服用核苷(酸)类药物治疗的慢性乙型肝炎患者206例为研究对象,按照入院先后顺序将其分为对照组和观察组各103例,对照组患者按常规住院宣教及出院指导,观察组患者在对照组患者的基础上实施有针对性的延续性护理,时间为12个月。比较两组患者药物管理能力和服药依从性、复查率、出院12个月内的再次入院率及观察组患者对延续性护理的满意度。结果两组患者无论是在药物管理还是服药依从性上均出现随着出院时间的推移,差异度明显扩大,具有统计学意义(P<0.05或P<0.01)。两组患者在出院后1、12个月时复诊情况的差异无统计学意义(P>0.05);出院后3、6、9个月时复诊情况的差异均有统计学意义(均P<0.01),两组患者在出院12个月中的再次入院率有统计学意义(P<0.05)。观察组在出院12个月时对延续性护理的评价高。结论延续性护理能有效提高慢性乙型肝炎患者服用核苷(酸)类药物的依从性和对疾病管理能力,减少再次入院率,节约了卫生服务成本,同时还能提高患者对护理服务的满意度。

核苷类抗乙型肝炎病毒药物研究进展

乙型肝炎病毒严重危害人类健康,抗乙型肝炎病毒药物的研究是当今全球药物研发的热点。本文通过国内外文献检索,重点从结构特点、作用机制、体内外活性评价和临床应用等方面,对核苷类抗乙型肝炎病毒药物进行比较和评价,并展望了中国乙型肝炎病毒药物研究所面临的机遇和挑战。